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    How To Protect The Brain In Old Age (and Stop Alzheimer's)
    By Catarina Amorim | April 11th 2013 04:42 AM | 5 comments | Print | E-mail | Track Comments
    About Catarina

    After many years as a scientist (immunology) at Oxford University I moved into scientific journalism and public understanding of science. I am...

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    Scientists in the UK, Portugal and Germany solved the structure of kynurenine 3-monooxygenase (KMO), a protein implicated in the neurodegeneration (destruction of nerve cells) seen in diseases associated with old age, such as Alzheimer’s, Parkinson’s and Huntington’s.

     It also reveals how to block KMO in a major first step to develop a promising new therapeutic approach for a group of diseases that, despite affecting millions worldwide, remain without cure or treatment. 

    “Neurodegenerative diseases linked to old age are rising non-stop and need urgent control. KMO-targeted approaches should be particularly valuable because they will help, not one, but several of these conditions,” says Marta Amaral, first author of the study. 

    Old lady at San Miguel Allende, Guanajuato, Mexico. Credit: Tomas Castelazo

    KMO is a protein, part of a cascade of reactions called kynurenine path (KP), which is known to be able to cause neurodegeneration. The cascade breakdowns tryptophan - an important molecule for brain activity - into a series of metabolites, some of which are neuroprotective (the metabolite called KYNA), while others are toxic to the nerve cell (called 3-HK and QUIN). 

    The theory is that with age the balance moves towards more neurotoxic compounds leading to the neurodegeneration seen in diseases linked to aging.

    Supporting this idea not only the neurotoxic HK and QUIN are found in abnormally high quantities in the brain of neurodegenerative patients, but also, when injected into animals, reproduce many of the pathological features and chemical impairments typical of neurodegenerative diseases. The levels of KYNA (which is neuro-protective), on the other hand, are low in these patients’ brains. 

    What this suggests is that correction of the neurotoxic/neuroprotective imbalance could be beneficial in stopping the brain destruction linked to aging (and old people's neurodegenerative diseases).

    And for that KMO is the perfect target -it seats at the branching point between the two possible outcomes, catalyzing  the neurotoxic arm of KP. So its inhibition/blocking should swerve tryptophan breakdown towards the neuroprotective product (KYNA).

    And indeed, blocking KMO ameliorates symptoms in several animal models of Huntington’s and Alzheimer’s disease, and this in animals asdifferent as fruit flies, yeast and even mice. A problem for its use inpatients, though, is that none of the existing KMO inhibitors can enter the brain easily limiting their therapeutic worth in humans. It is here that Marta Amaral, a doctoral student co-supervised by researchers Nigel Scrutton, Flaviano Giorgini, and TiagoOuteiro - steps in.

    The researcher used a crystallography to determine KMO structure - creating crystals from biological molecules and then analyze them by X-rays is probably the most advanced technique available to obtain structural information about biological active molecules. The x-ray allows to see them as they look in “real life”,when they are functional, and so to understand better how these molecules work.

    In the study to be published Amaral and colleagues describe the first crystal structure ofKMO binding its inhibitor UPF648. UPF648 can improve (in animals) the symptoms of Huntington’s disease, a neurodegenerative genetic disorder (linked to aging) that affects muscle coordination and creates cognitive decline and psychiatric problems. This is believed to happen because, even if UPF648 cannot enter the brain, the KP metabolites formed can. So as KMO is inhibited and the neuroprotective KYNA quantity increases, KYNA enters the brain, switching its balance towards neuroprotection.

    But with the new results identifying where and how KMO can be blocked, scientists can now try to develop inhibitors that actually enter the brain. This will no doubt increase enormously their therapeutic effectiveness what is great news. After all, neurodegenerative conditions linked to old age are on the fast rise in developed countries where the aging population is growing without stop. At the moment, 16% of all Europeans are already over 65 (the moment when these diseases’ incidence increases abruptly), with numbers expected to reach 25% by 2030. And these come with serious financial burden – just in the UK dementia alone is costing the state £17 billion pounds a year.

    The work was a collaboration between the University of Manchester, the University of Leicester University, UK, and the Institute of Molecular Medicine in Lisbon, Portugal, and the University Medical Center Goettingen, Germany.

    Citation:   Marta Amaral,Colin Levy, Derren J. Heyes, Pierre Lafite, Tiago F. Outeiro, FlavianoGiorgini, David Leys and Nigel S. Scrutton , Structural basis of inhibition in the neurodegeneration target kynurenine 3-monooxygenase Nature DOI: 10.1038/nature12039

    Comments

    Greg M.
    This is very promising. I hope further research into residue conservation (e.g., Arg83) will provide greater insight into KMO inhibition. The fact that previous studies involving KMO inhibitors in animal models achieved any success without penetrating the blood-brain barrier is quite revealing. Thanks for sharing.
    Begin with this assumption: it's all a joke. Then you will see the humour in everything.
    Bonny Bonobo alias Brat
    Am I missing something here, like how to protect the brain in old age (and stop Alzheimer's)?
    My article about researchers identifying a potential blue green algae cause & L-Serine treatment for Lou Gehrig's ALS, MND, Parkinsons & Alzheimers is at http://www.science20.com/forums/medicine
    amorca

    In all these diseases Helen the neurodegeneration is a continuous and normally a very slow process triggered by age. If in fact this pathway is behind the destruction of the nerve cells   like it seems, KMO inhibition will create a neuroprotective environment and avoid it. Once you stop the neurodegeneration/avoid it to appear you prevent the diseases from appearing, including Alzheimer's .
    Bonny Bonobo alias Brat
    Thanks for replying Catarina. Yes I understand quite a lot about these neurodegenerative diseases after caring for my mother while she was dying from motor neurone disease and quite a few of my friend's parents have or have died while suffering from dementia.

    What I was asking was how can we utilise this KMO inhibition in practical ways now to  help current sufferers? The title of this blog implies that the methodology already exists, maybe it should have had a question mark on the end? A lot of people will Google and find this title and blog, thinking we already have the methodolgy to do this when I don't think we do yet, or do we?
    My article about researchers identifying a potential blue green algae cause & L-Serine treatment for Lou Gehrig's ALS, MND, Parkinsons & Alzheimers is at http://www.science20.com/forums/medicine
    In my own analyze, the main problem with kynurenine 3-monooxygenase (KMO) is the unsatured *oxygeno adductase reaction* over the *mono oxygenase* molecule, that is part of systemic body failure thru the complete nerve systems of brain when faced to ageing. Part of the solution is first, finding a way in which human brain could improve electric inductance over brain, and second, allow kynurenine 3-monooxygenase to complete its *oxygenase adductance* thru a supplementary oxydation covalent construction to become kynurenine 3-dioxygenase (KDO) thru a 2-OH base. Hope there is here a way to succeed in fighting this intolerable disease. (Complementarize your *diet* with *non toxic electric catalyzers* such as *Chrome FTG*)